Extracellular adenosine in acute stress-induced depressive-like behavior: Where does it come from?

Major depressive disorder (MDD) is a prevalent psychiatric disease, and understanding its neurochemical basis is crucial for developing new treatments. Acute stress models are often used to study behaviors relevant to depression. This study investigated the source and role of extracellular adenosine in the ventral hippocampal CA1 region during acute stress-induced depressive-like behavior. Using fiber photometry with GRAB fluorescent sensors (GRABATP1.0 and GRABAdo1.0) in mice, we monitored real-time dynamics of adenosine and ATP in response to tail suspension test (TST) and foot shock (FS). Both stressors significantly increased extracellular adenosine levels, while only FS elevated ATP. Pharmacological blockade revealed distinct adenosine sources: TST-induced adenosine primarily originated from ENT1/2-mediated transmembrane efflux, whereas FS-derived adenosine involved both ENT1/2 transport and CD73-dependent ATP hydrolysis. Behaviorally, inhibiting both pathways alleviated FS-induced depressive phenotypes, and exogenous ATP/adenosine administration in the CA1 region exacerbated depressive-like behaviors (e.g., increased immobility in TST, reduced exploration). These findings establish that distinct sources of extracellular adenosine in the ventral hippocampal CA1 region contribute to acute stress induced depressive-like behavior. This work improves our understanding of purinergic signaling in stress responses and may inform future research into novel therapeutic strategies for mood disorders.